The present invention generally relates to metal mesoporphyrin halide compounds and processes for their preparation. More specifically, it relates to processes for making novel intermediate compounds which can be converted to such mesoporphyrin halide compounds.
Tin (IV) mesoporphyrin IX dichloride or stannsoporfin is a chemical compound having the structure indicated in FIG. 1. It has been proposed for use, for example, as medicament in the treatment of various diseases including, for example, psoriasis (U.S. Pat. No. 4,782,049 to Kappas et al.) and infant jaundice (for example, in U.S. Pat. Nos. 4,684,637, 4,657,902 and 4,692,440). Stannsoporfin is also known to inhibit heme metabolism in mammals, to control the rate of tryptophan metabolism in mammals, and to increase the rate at which heme is excreted by mammals (U.S. Pat. Nos. 4,657,902 and 4,692,400 both to Kappas et al.).
Processes for obtaining stannsoporfin are known in the art. Protoporphyrin IX iron (III) chloride or hemin, of the structural formula indicated in FIG. 2, is commonly used as starting material. The hemin is generally hydrogenated to form an intermediate mesoporphyrin IX dihydrochloride, which is subsequently subjected to tin insertion, yielding stannsoporfin.
One prior method for the preparation of the intermediate mesoporphyrin IX dihydrochloride has involved catalytic hydrogenation of hemin over Pd(0) in formic acid at elevated temperature. Column chromatography of the resulting intermediate obtained by such a method yields an intermediate mesoporphyrin IX dihydrochloride product that reportedly contains about 15% of an unidentified impurity. Another preparation method for this intermediate has been typically performed at lower temperatures with heating hemin in formic acid in the presence of palladium catalyst. This process is reported to reduce the amount of the unidentified impurity; however, the reaction is difficult to drive to completion without decomposition of the intermediate product.
The above referenced methods for the preparation of the mesoporphyrin IX intermediate are used to produce only small, gram scale quantities of the product, and the product further requires subsequent isolation and purification, generally by preparative or column chromatography. Additionally, those methods in which hydrogenation is carried out at lower temperatures yield incomplete reactions, and when higher temperatures are used, degradation of the intermediate product is observed. Consequently, the crude intermediate product requires purification. Furthermore, the above referenced procedures require exceedingly high solvent volumes, thus making the process unsuitable for industrial scale up, since isolation of mesoporphyrin IX dihydrochloride or its free base is performed using a filtration process. Such filtrations and subsequent washings of the products are time-consuming, making the large-scale isolations costly and difficult. Additionally, the limited stability of mesoporphyrin IX in hydrochloric acid at the elevated temperatures required to form the dihydrochloride also complicates the industrial scale up of this process.
The insertion of various metals into porphyrin rings, including the insertion of tin into mesoporphyrin IX, has been described by Fischer and Neumann (Ann. Chem. (1932), 494, 225). The reaction for the insertion of tin is performed in an acid, typically acetic acid, and further typically under reflux, using Sn (II) in the presence of an oxidant. A modified process is also described by Fuhrhop and Smith, as reported in xe2x80x9cPorphyrins and Metalloporphyrinsxe2x80x9d p. 757, Elsvier, Amsterdam, 1975, to include sodium acetate, which buffers the solution and enhances deprotonation of the porphyrin. In most cases, the metal mesoporphyrin halide product crystallizes directly from the reaction mixture on cooling. Such crystallization may be enhanced by the addition of water or methanol.
It is an object of the present invention to provide a novel process for the preparation of metal mesoporphyrin halides that overcomes some of the difficulties of the processes known in the art.
It is a further object of the invention to provide a novel intermediate useful in the preparation of tin mesoporphyrin chloride and other metal mesoporphyrin halides.
It has now been discovered that, if the catalytic hydrogenation of hemin is conducted in formic acid, in two distinct states, each using different reaction conditions, a novel intermediate compound, a mesoporphyrin IX formate, is formed. This compound can be precipitated so that it can be isolated in a substantially pure, solid form. Then the substantially pure intermediate can be reacted to insert metals such as tin, and obtain metal mesoporphyrin halides with a high degree of purity, capable of further purification if necessary, by simple procedures capable of being conducted on an industrial scale.
Thus the invention provides, from a first aspect, a process of preparing a mesoporphyrin IX formate, which comprises subjecting hemin to catalytic hydrogenation in formic acid, said hydrogenation being conducted in two successive steps comprising:
the first step of subjecting a mixture of hemin and a hydrogenation catalyst in formic acid to hydrogen pressure of about 30-60 psi then raising the temperature to about 85-95xc2x0 C., and maintaining the temperature within that range for a period of about 1-3 hours;
the second step of subjecting said mixture to further hydrogen pressure of about 30-60 psi at temperatures of about 45-50xc2x0 C. for a period of about 3-6 hours; and
recovering the mesoporphyrin IX formate from the reaction mixture by precipitation with an ether or other organic solvent.
Mesoporphyrin IX formate, which has the following structural chemical formula indicated in FIG. 3, is a novel chemical compound, and constitutes a second aspect of the present invention.
Alternatively and preferably, the reactor may be pressurized with H2 gas prior to the heating step. Pressurizing the reactor with hydrogen prior to heating, in the first step of the process, reduces degradation, while exceeding the times and the temperatures set out above for the first step increases degradation. On the other hand, shorter reaction times and lower temperatures will lead to undesirable decreases in conversion, leading to low product yields.
The second step as defined above completes the conversion of the hemin (protoporphrin IX) to mesoporphyrin IX formate.
Isolation of the intermediate product as a formate provides a readily filterable intermediate, filtering and washing of which to obtain at least a substantially high purity intermediate product (about  greater than 97%) is a simple procedure. The purity of the intermediate is important in the manufacturing of the final product, whether stannsopofin or other metal mesoporphyrin halides, in that a higher purity intermediate produces a higher purity product.
A second process aspect of the present invention comprises a process of converting a mesoporphyrin IX formate, to a metal mesoporphyrin halide which comprises:
drying the mesoporphyrin IX formate;
subjecting the mesoporphyrin IX formate, to a chemical metal insertion process by reaction with a metal halide compound, under buffered, acidic reaction conditions and in the presence of an oxidant; and
recovering the metal mesoporphyrin halide from the reaction mixture.
The invention provides, from a third aspect, a process of purification of a metal mesoporphyrin halide, which comprises the steps of:
(a) dissolving the metal mesoporphyrin halide in an aqueous basic solution to obtain a dissolved metal mesoporphyrin halide;
(b) treating said dissolved metal mesoporphyrin halide with charcoal to obtain a treated metal mesoporphyrin halide;
(c) adding said treated metal mesoporphyrin halide to a first aqueous acid solution to obtain a precipitated metal mesoporphyrin halide;
(d) triturating said precipitated metal mesoporphyrin halide in a second aqueous acid solution at elevated temperature to obtain a pharmaceutical grade pure (about or more than 97%) metal mesoporphyrin halide; and
(e) drying the pharmaceutical grade pure metal mesoporphyrin halide.
A fourth aspect of the invention comprises a process of preparing a metal mesoporphyrin halide, which comprises subjecting hemin to a two step catalytic hydrogenation comprising:
the first step of subjecting a mixture of hemin and a hydrogenation catalyst in formic acid to hydrogen pressure of about 30-60 psi then raising the temperature to about 85-95xc2x0 C., and maintaining the temperature within that range for a period of about 1-3 hours;
the second step of subjecting said mixture to further hydrogen pressure of about 30-60 psi at temperatures of about 45-50xc2x0 C. for a period of about 3-6 hours;
recovering the mesoporphyrin IX formate from the reaction mixture by precipitation with an ether or other organic solvent;
drying the mesoporphyrin IX formate;
subjecting the mesoporphyrin IX formate, to a chemical metal insertion process by reaction with a metal halide compound, under buffered, acidic reaction conditions and in the presence of an oxidant; and
recovering the metal mesoporphyrin halide from the reaction mixture.
In accordance with an embodiment of this fourth aspect, the process can further comprise the purification steps of:
(a) dissolving the metal mesoporphyrin halide in an aqueous basic solution to obtain a dissolved metal mesoporphyrin halide;
(b) treating said dissolved metal mesoporphyrin halide with charcoal to obtain a treated metal mesoporphyrin halide;
(c) adding said treated metal mesoporphyrin halide to a first aqueous acid solution to obtain a precipitated metal mesoporphyrin halide;
(d) triturating said precipitated metal mesoporphyrin halide in a second aqueous acid solution at elevated temperature to obtain a substantially pure (about or more than 95%) metal mesoporphyrin halide; and
(e) drying said substantially pure metal mesoporphyrin halide.
In all the embodiments of the fourth process aspect according to the invention, steps (a) to (c) may be carried out at least twice prior to subjecting the precipitated metal mesoporphyrin halide to step (d).